The mucosal immune system must simultaneously decipher pathogens from innocuous flora and maintain self tolerance while promoting long-lasting immunity to pathogens. In the gut, and especially the large intestine, this is a considerable task, where the commensal microbes comprise approximately 1012 cells per gram contents. We have characterized oral infection by Salmonella in C57BL/6, A/J and 129S1 mice, and demonstrated that this infection progresses toward 3 distinct outcomes. C57BL/6 mice gradually develop cecal infection but are rapidly overwhelmed by systemic infection. A/J mice develop rapid colonization of the cecum followed by chronic persistent infection and inflammation. 129S1 mice gradually develop cecal infection and inflammation, and proceed to resolve the infection and inflammation. We hypothesize that host genetic differences are major determinants of these divergent outcomes. In this proposal, we will use a two pronged approach to decipher important functional and genetic differences that contribute to mucosal defenses against bacterial pathogens. In the first aim, we will thoroughly characterize oral Salmonella infection in C57BL/6, 129S1 and A/J mice, through quantification of bacterial burden, quantitative histology, molecular assays of key immunological factors, and immunological assays of T and B lymphocyte responses. These studies will identify molecular and immunological factors that correlate with the control of bacterial replication and inflammation. In the second aim, we will identify A/J chromosomes that contribute to early cecal colonization and increased inflammation in A/J mice, using a panel of consomic mice, which harbor single A/J chromosomes on the C57BL/6 background. These studies will systematically define genetic differences between A/J and C57BL/6 mice that control mucosal immune defenses against Salmonella. Both of these aims will lead to the identification of novel molecular pathways, candidate genes and chromosomal loci that influence mucosal immunity. In this proposal, we will perform detailed studies to characterize molecular and genetic factors that regulate mucosal infection and inflammation. Our results will provide insight and pave the way for future studies aimed at developing a detailed model of mucosal defense to infection, improve mucosal vaccines, and treat intestinal inflammatory disorders. These studies should reveal mechanisms that control tolerance to commensal bacteria in the setting of infections, and permit the acquisition of specific and effective immunity to mucosal pathogens. Though many questions remain to be answered about mucosal immunity, this model system provides a valuable opportunity to dissect the contribution genetic factors from both host and pathogen to the control of persistent bacterial infections and mucosal inflammation.